AXL-TBK1 driven AKT3 activation promotes metastasis.

Area of Science:

• Oncology
• Molecular Biology
• Cancer Signaling Pathways

Background:

• The receptor tyrosine kinase AXL drives tumor progression, metastasis, and therapy resistance.
• AXL induces epithelial-mesenchymal transition (EMT), a key process in cancer spread.

Purpose of the Study:

• To elucidate the downstream signaling pathway activated by AXL that promotes EMT.
• To investigate the role of AKT3 in AXL-mediated EMT and cancer progression.

Main Methods:

• Investigated AXL-induced phosphorylation of TANK-binding kinase 1 (TBK1).
• Assessed the interaction and phosphorylation of AKT3 by TBK1, dependent on mTORC1.
• Examined AKT3's role in Snail nuclear accumulation and EMT marker expression.
• Analyzed AKT3 and Snail co-localization in human pancreatic ductal adenocarcinoma tissues.
• Evaluated the impact of AKT3 deficiency on metastasis in mouse models.

Main Results:

• AXL activation led to TBK1 phosphorylation and downstream activation of AKT3 and Snail.
• TBK1 directly bound and phosphorylated AKT3, a process dependent on the mTORC1 complex.
• Activated AKT3 promoted Snail nuclear accumulation, enhancing EMT.
• Nuclear AKT3 and Snail co-localized in human pancreatic tumors and correlated with poor outcomes.
• AKT3-deficient mouse pancreatic cancer cells exhibited reduced metastatic spread.

Conclusions:

• The AXL-TBK1-AKT3-Snail axis is a critical pathway for EMT induction and cancer progression.
• Nuclear AKT3 is a potential biomarker for aggressive pancreatic cancer.
• Targeting AKT3 presents a promising therapeutic strategy for inhibiting EMT in aggressive cancers.